The NLRP3 Inflammasome is Involved in the Pathogenesis of Parkinson’s Disease in Rats

Mao, Zhijuan; Liu, Chanchan; Ji, Suqiong; Yang, Qingmei; Ye, Hongxiang; Han, Huiying; Xue, Zhenyi

doi:10.1007/s11064-017-2185-0

Cited by 137 publications

(92 citation statements)

References 51 publications

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“…Moreover, rats treated with LPS and 6‐OHDA, along with Ac‐YVAD‐CMK, a caspase‐1 inhibitor, the expression of NLRP3 inflammasome components was inhibited in tissue collected from the SNpc, motor deficits were reversed, and loss of dopaminergic neurons was prevented. This demonstrates the possible link between NLRP3 inflammasome‐mediated inflammation and dopaminergic neuronal loss in PD . The study did not investigate and compare the activation of the NLRP3 inflammasome and release of proinflammatory cytokines in the microglia or astrocytes in the SNpc tissue samples.…”

Section: Nlrp3 Inflammasome‐mediated Inflammatory Pathways In Pdmentioning

confidence: 97%

“…This demonstrates the possible link between NLRP3 inflammasome-mediated inflammation and dopaminergic neuronal loss in PD. 54 The study did not investigate and compare the activation of the NLRP3 inflammasome and release of proinflammatory cytokines in the microglia or astrocytes in the SNpc tissue samples. Previously, it was thought that the NLRP3 inflammasome was present in astrocytes.…”

Section: Nlrp3 Inflammasome-mediated Inflammatory Pathways In Pdmentioning

confidence: 99%

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Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

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Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson's disease (PD). Components of the nucleotide‐binding oligomerization domain and leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome complex, leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3, caspase‐1, and apoptosis‐associated speck‐like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α‐synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and release of interleukin‐1β and interleukin‐18 caspase‐1‐mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society

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Section: Nlrp3 Inflammasome‐mediated Inflammatory Pathways In Pdmentioning

confidence: 97%

Section: Nlrp3 Inflammasome-mediated Inflammatory Pathways In Pdmentioning

confidence: 99%

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

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“…α‐Synuclein was shown to trigger activation of the NLRP3 inflammasome in human monocytes and BV2 microglial cells (Codolo et al , ; Gustot et al , ; Zhou et al , ), but not in primary microglia (Gustin et al , ). In vivo , microinjection of the caspase‐1 inhibitor Ac‐YVAD‐CMK was shown to reduce the expression of NLRP3 inflammasome signaling proteins and improve the number of dopaminergic neurons in LPS‐induced and 6‐hydroxydopamine‐induced PD in rats (Mao et al , ). In agreement, NLRP3 knockout mice were resistant to the loss of nigral dopaminergic neurons induced by treatment with the neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), which was associated with a reduction in caspase‐1 activation and IL‐1β and IL‐18 secretion (Yan et al , ).…”

Section: Inflammasome Activation In Parkinson's Diseasementioning

confidence: 99%

Inflammasomes in neuroinflammatory and neurodegenerative diseases

et al. 2019

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Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid‐β, α‐synuclein, and prions, that can activate inflammasomes. Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host‐derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin ( IL )‐1β and IL ‐18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for inflammasome activation. However, additional CNS ‐resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate inflammasomes. In this review, we will discuss current understanding of the role of inflammasomes in common degenerative diseases of the brain and highlight inflammasome‐targeted strategies that may potentially treat these diseases.

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“…Nod-like receptor protein 3 (NLRP3) inflammasome can be activated by diverse stimuli, such as ATP, crystals, and endoplasmic reticulum (ER) stress, serving as a gate to produce mature IL-1β and involving multiple immune disorders [32][33][34][35][36][37][38][39][40][41][42][43]. The important role of NLRP3 inflammasome in mediating neurodegeneration produced by several toxins, including intracranial injection of LPS [44,45], has been described. However, how precisely NLRP3-IL-1β impacts endotoxemia-elicited acut-chronic neuroimmune phase transition, which dominates the following progressive neurodegeneration, is still unknown.…”

Section: Introductionmentioning

confidence: 99%

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration

Zhao

Wang

Zhou

et al. 2020

J Neuroinflammation

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Background: Sepsis-associated acute brain inflammation, if unresolved, may cause chronic neuroinflammation and resultant neurodegenerative diseases. However, little is known how the transition from acute to chronic neuroinflammation, which is critical for the following progressive neurodegeneration, occurs in sepsis. The goal of this study was to investigate potential immune factors regulating the transition process using a widely used endotoxemia LPS mouse model. This model shows distinct acute and chronic phases of neuroinflammation and recapitulates many cardinal features of Parkinson's disease, thus, providing a unique opportunity for studying phase transition of neuroinflammation.Methods: C57BL/6 J, NLRP3 −/− , and IL-1R1 −/− mice were employed. Mild and severe endotoxemia were produced by LPS ip injection at 1 or 5 mg/kg. Neuroinflammation in vitro and in vivo was assessed with proinflammatory cytokine expression by qPCR or ELISA and microglial activation by immunohistochemical analysis. Neurodegeneration was measured by manual and stereological counts of nigral dopaminergic neurons and immunohistochemical analysis of protein nitrosylation and α-synuclein phosphorylation. Results: LPS-elicited initial increases in mouse brain mRNA levels of TNFα, IL-6, IL-1β, and MCP-1, and nigral microglial activation were not dose-related. By contrast, the delayed increase in brain mature IL-1β levels was dependent on LPS doses and protracted nigral microglial activation was only observed in high dose of LPS-treated mice. LPS-elicited increase in brain mature IL-1β but not IL-1α level was NLRP3-dependent. After high dose LPS treatment, deficiency of NLRP3 or IL-1R1 did not prevent the initiation of acute neuroinflammation but abolished chronic neuroinflammation. Genetic or pharmacological inhibition of the NLRP3-IL-1β axis repressed LPS-stimulated upregulation of chronic neuroinflammatory mediators including MHC-II, NOX2, and Mac1, and protected dopaminergic neurons. Ten months after LPS-elicited severe endotoxemia, nigral persisted microglial activation, elevated nitrosylated proteins and phosphorylated α-synuclein, and significant neuronal degeneration developed in wild-type mice but not in NLRP3 −/− or IL-1R1 −/− mice.

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The NLRP3 Inflammasome is Involved in the Pathogenesis of Parkinson’s Disease in Rats

Cited by 137 publications

References 51 publications

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

Inflammasomes in neuroinflammatory and neurodegenerative diseases

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration

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